A preparation method of mitiglinide calcium intermediate

Abstract

The invention provides a method for preparing a mitiglinide calcium intermediate. The method comprises the following steps: S-benzylsuccinic acid, a condensing agent, cis-perhydroisoindole or a salt thereof, and benzyl alcohol are reacted in one step to generate mitiglinide benzyl ester. The reaction method has high yield, low cost, simple operation, safety, environmental protection, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for preparing a mitiglinide calcium intermediate. Background Art

[0002] Mitiglinide calcium was synthesized by Kikyo Pharmaceutical Co., Ltd. in Japan. In December 2002, it was approved for use in type 2 diabetes patients to control postprandial blood sugar levels, and was launched in Japan in April 2004. Kikyo Pharmaceutical licensed the drug to Choongwae in South Korea, Servier in France, and Takeda in Japan in March 2003. These are currently in the preclinical, Phase III, and registration stages, respectively. Meanwhile, Phase III trials are underway in the United States, Canada, and Mexico, as well as in Europe, Africa, and other regions, licensed to Servier in France.

[0003] The Japanese Pharmacopoeia of Mitiglinide Calcium has extremely high requirements for impurity levels, stipulating that individual impurities are ≤0.1% and total impurities are ≤0.15%. Although there are many synthetic process routes, they can be divided into three categories based on ester formation and ester type: the first category is to directly synthesize Mitiglinide Calcium without ester formation. Although this method is simple, it cannot solve the problem of difficult purification of Mitiglinide Calcium; the second category is the method of forming methyl ester. This method has an extremely low yield and requires column chromatography purification, which makes it difficult to achieve large-scale production; the third category is to form benzyl ester and then hydrolyze it into salt to obtain Mitiglinide Calcium. This is also the most reported route to obtain high-purity Mitiglinide Calcium. The benzyl ester intermediate in this route has a strong ability to remove process impurities, and impurities are almost undetectable. Finally, by hydrolyzing and forming calcium salts to remove easily removable by-products, extremely pure Mitiglinide Calcium API can be obtained. Therefore, forming benzyl ester is the key impurity removal step in the synthesis of Mitiglinide Calcium. This method mainly includes two steps:

[0004] Step 1: S-benzylsuccinic acid is reacted with a halogenating agent (thionyl chloride and imidazole system) or a condensing agent to obtain an active intermediate, which is reacted with cis-perhydroisoindole, and the by-products are removed by post-treatment to obtain mitiglinide acid;

[0005] Step 2: reacting mitiglinide acid with benzyl halide under alkaline conditions to obtain mitiglinide acid benzyl ester.

[0006] Although this route has a good effect on removing impurities, it still has many disadvantages. First, the dibenzyl halide in the step is a genotoxic reagent, which is highly harmful to the human body and is highly irritating when added. Therefore, its use in the pharmaceutical field should be avoided as much as possible; second, the reaction is carried out in two steps, and two post-treatments are performed, which wastes a large amount of solvents and reagents and is not conducive to environmental protection; third, the two treatments cause certain losses and the total yield is low. Summary of the Invention

[0007] In view of the above problems, the present application provides a method for preparing mitiglinide calcium key intermediate mitiglinide benzyl ester with high purity, high yield and simple operation. The method completes the preparation of mitiglinide benzyl ester in only one reaction system. The reaction scheme is as follows:

[0008]

[0009] The method comprises the following steps:

[0010] Step 1: S-benzylsuccinic acid reacts with a condensing agent in an organic solvent;

[0011] Step 2: adding cis-perhydroisoindole or its salt to the reaction system of step 1 to react to obtain a mitiglinide acid acyl active intermediate;

[0012] Step 3: adding benzyl alcohol to the reaction system of step 2 and performing reflux reaction; adjusting the reaction system to acidity after the reaction is completed; separating the organic phase to obtain a crude product of benzyl mitiglinide;

[0013] Step 4: purifying the crude product of mitiglinide acid benzyl ester obtained in step 3 to obtain mitiglinide acid benzyl ester.

[0014] Preferably, the molar ratio of S-benzylsuccinic acid to the condensing agent is 1:1.9-2.5.

[0015] Preferably, the molar ratio of S-benzylsuccinic acid: cis-perhydroisoindole or its salt: benzyl alcohol is 1:0.8-2:0.8-5; more preferably, the molar ratio of S-benzylsuccinic acid: cis-perhydroisoindole or its salt: benzyl alcohol is 1:0.9-1.5:0.9-3.

[0016] Preferably, the condensing agent in step 1 is selected from any one of N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, N,N'-disuccinimidyl carbonate, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, or a mixture thereof; the condensing agent may also be a combination of a halogenating agent and imidazole, and the halogenating agent is selected from any one of thionyl chloride, oxalyl chloride, phosphorus oxychloride, and phosphorus pentachloride, or a mixture thereof.

[0017] Preferably, the organic solvent in step 1 is selected from a mixture of one or more of ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile, acetone, DMF, DMSO, toluene, butyl acetate, and isopropyl acetate. Furthermore, the volume of the organic solvent used is 1 to 20 times the mass of S-benzylsuccinic acid, more preferably 2 to 10 times.

[0018] Preferably, the reaction time of step 1 is 5 minutes to 3 hours.

[0019] Preferably, the step 2 of adding cis-perhydroisoindole or its salt is performed by dropwise addition. Adding cis-perhydroisoindole or its salt by dropwise addition can further improve the reaction yield.

[0020] Preferably, the reaction temperature in step 2 is from -10°C to reflux temperature, and the reaction time is from 5 minutes to 8 hours.

[0021] Preferably, the reaction temperature in step 3 is 10° C. to reflux temperature, and the reaction time is 1 to 40 hours.

[0022] Preferably, the refining process in step 4 is to add ethyl acetate, heat to dissolve, and cool to crystallize to obtain a refined product.

[0023] Beneficial effects of this application:

[0024] In this application, after S-benzylsuccinic acid reacts with a condensing agent and cis-perhydroisoindole to form a reactive intermediate of the mitiglinide acid acyl group, the reaction solution is directly added with benzyl alcohol to react without post-treatment to obtain the target product. Impurities can be substantially removed through acid and water washing and further purification, resulting in a high-purity final product. In other words, the reaction method of this application completes the preparation of mitiglinide acid benzyl ester in only one reaction system, overcoming the cumbersome steps of the prior art requiring a two-step reaction and two post-treatments. It is simple to operate, has a short reaction time, and requires less equipment. In addition, the preparation method of this application avoids the use of genotoxic reagents such as benzyl bromide or benzyl chloride, reducing the damage to the human body and the environment, making it more suitable for large-scale industrial production.

[0025] The preparation method of the present application can achieve a high yield of 85%, and the purity of the prepared product reaches 99.8%, which is significantly better than the existing technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Various other advantages and benefits will become apparent to those skilled in the art upon reading the detailed description of the preferred embodiment below. The accompanying drawings are for illustration purposes only and are not to be considered as limiting the present invention. The same reference symbols are used throughout the drawings to represent the same components. In the drawings:

[0027] Figure 1 Hydrogen spectrum of mitiglinide acid benzyl ester prepared in this application DETAILED DESCRIPTION

[0028] Exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although exemplary embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the present invention to those skilled in the art.

[0029] Example 1

[0030] To a reaction flask, add 360 ml of ethyl acetate, 140.18 g of N,N-carbonyldiimidazole, and 90.00 g of S-benzylsuccinic acid at room temperature. The mixture is allowed to react for 1 hour at room temperature. 54.03 g of cis-perhydroisoindole is then added dropwise. The reaction is continued at room temperature for 3 hours. 70.12 g of benzyl alcohol is added and the mixture is refluxed for 5 hours. 2 mol / L hydrochloric acid is added dropwise to adjust the pH to acidic. The layers are separated, and the organic phase is washed with 360 ml of water. 200-300 ml of solvent is recovered under reduced pressure. 450 ml of n-hexane is added to the residue, followed by crystallization at 0-10°C for 4 hours. Filter and dry to obtain 168.04 g of a crude product.

[0031] The crude product was dissolved by heating with 410 ml of ethyl acetate, then cooled to 0-10°C and stirred for crystallization for 3 h, filtered, and the filter cake was dried to obtain 148.01 g of refined benzyl mitiglinide.

[0032] Total yield: 84.4%; purity: 99.7%.

[0033] 1 H-NMR (CDCl3, 400MHz) δppm: 1.35~1.58 (8H, m), 2.12~2.13 (2H, m), 2.20~2.22 (1H, m), 2.28~2.32 (1H, m), 2.59~2.68(1H,m), 2.82~2.88(1H,m), 3.01~3.43(5H,m), 5.03~5.16(2H,m), 7.13~7.34(10H,m), see attachment Figure 1 .

[0034] Example 2

[0035] Add 8 L of dichloromethane to a reaction flask. Add 4.1 kg of N,N-carbonyldiimidazole and 2.1 kg of S-benzylsuccinic acid at room temperature and react at room temperature for 1 hour. Then, dropwise add a mixture of 1.5 kg of cis-perhydroisoindole hydrochloride and 2 L of dichloromethane. After completion of the addition, react at room temperature for 4 hours. Add 2.2 kg of benzyl alcohol and reflux for 10 hours. Adjust the pH to acidic by dropwise addition of 2 mol / L hydrochloric acid. Separate the layers, wash the organic phase with 8 L of water, and recover the solvent under reduced pressure. Dissolve the residue in 2 L of ethyl acetate and 10 L of n-hexane. Cool to 10-20°C to allow crystallization for 3 hours. Filter and dry to obtain 4.0 kg of crude product.

[0036] The crude product was added to 10 L of ethyl acetate and heated to dissolve, then cooled to 0-10 ° C for crystallization for 3 h, filtered and dried to obtain 3.5 kg of refined mitiglinide acid benzyl ester.

[0037] The total yield is 85.6%. The purity is 99.8%.

[0038] Example 3

[0039] Dissolve 21.25g of triethylamine in 104ml of ethyl acetate, add 7.15g of imidazole and 10.41g of S-benzylsuccinic acid with stirring, then add 12.49g of thionyl chloride dropwise at -20--10°C. After reacting for 4 hours at -15-0°C, add 6.25g of perhydroisoindole dropwise. Warm the mixture to room temperature and react for 6-12 hours. Add 10.82g of benzyl alcohol and reflux for 6-18 hours. After the reaction, adjust the pH to below 3 with 2mol / L hydrochloric acid. Separate the mixture, wash the organic phase with 40ml of water, and recover 80-100ml of solvent under reduced pressure. Dissolve the residue in 50ml of n-hexane, cool to 10-20°C, crystallize for 3 hours, filter, and dry to yield 17.55g of crude product.

[0040] The crude product was added with 44 ml of ethyl acetate and heated to dissolve, then cooled to 0-10°C for crystallization for 3 h, filtered and dried to obtain 15.90 g of refined benzyl mitiglinide.

[0041] The total yield is 78.4%. The purity is 99.7%.

Claims

1. A method for preparing a mitiglinide calcium intermediate, characterized in that: The method comprises the following steps: Step 1: S-benzylsuccinic acid reacts with a condensing agent, N,N'-carbonyldiimidazole, in an organic solvent; Step 2: adding cis-perhydroisoindole or its salt to the reaction system of step 1 to react to obtain a mitiglinide acid acyl active intermediate; Step 3: adding benzyl alcohol to the reaction system of step 2 and performing reflux reaction; adjusting the reaction system to acidity after the reaction is completed; separating the organic phase to obtain a crude product of benzyl mitiglinide; Step 4, refining the crude product of mitiglinide acid benzyl ester obtained in step 3 to obtain mitiglinide acid benzyl ester; The reaction time of step 1 is 5 minutes to 3 hours; the reaction temperature of step 2 is -10°C to reflux temperature, and the reaction time is 5 minutes to 8 hours; the reaction temperature of step 3 is 10°C to reflux temperature, and the reaction time is 1 to 40 hours; The molar ratio of S-benzylsuccinic acid to the condensing agent N,N'-carbonyldiimidazole is 1:1.9~2.5; The molar ratio of S-benzylsuccinic acid: perhydroisoindole or its salt: benzyl alcohol is 1:0.8~2:0.8~5; The organic solvent in step 1 is ethyl acetate or dichloromethane.

2. The preparation method according to claim 1, wherein The molar ratio of S-benzylsuccinic acid: cis-perhydroisoindole or its salt: benzyl alcohol is 1:0.9~1.5:0.9~3.

3. The preparation method according to claim 1 or 2, wherein The fourth step of the refining process is to add ethyl acetate, heat to dissolve, cool and crystallize to obtain a refined product.

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